AG490 promotes HIF-1α accumulation by inhibiting its hydroxylation.

AG490 is a tyrphostin originally described as a Janus Activated Kinase (JAK) 2 inhibitor. AG490 also inhibits epidermal growth factor receptor (EGFR) and guanylyl cyclases (GC). More recently, AG490 was associated with oxidative stress protection in experimental acute kidney injury models. We now show that AG490 is also a strong activator of the Hypoxia Inducible Factor (HIF)-1. Under normoxic conditions HIF-1α is degraded through hydroxylation, von Hippel Lindau protein (VHL)-mediated ubiquitin tagging and proteasomal degradation. AG490 increased HIF-1α protein, but not HIF-1α mRNA levels, dose- and time-dependently in cultured endothelial, vascular smooth muscle and kidney proximal tubular epithelial cells. AG490 increased HIF-1α protein half-life, suggesting that HIF-1α protein accumulation resulted from a decreased degradation. In this regard, AG490 prevented HIF-1α hydroxylation and increased HIF-1α protein levels in human renal carcinoma cells expressing VHL, but did not further increase HIF-1α in VHL negative cells. AG490 did not prevent the proteasomal degradation of other proteins. HIF-1α was not upregulated by dominant negative JAK2constructs, tyrphostin AG9, the EGFR inhibitors erbstatin and genistein, the GC inhibitor Ly83583 or cGMP analogues. Finally, AG490 also increased HIF-1α transcriptional activity evidenced by the increased HIF-1α-dependent VEGF expression. In conclusion, AG490 is a novel HIF-1α activator that increases HIF-1α half-life and protein levels through interference with HIF-1α hydroxylation and VHL-mediated degradation. This action may contribute to the cell and tissue protective effects of AG490.

Nephrotic syndrome complicating chronic visceral leishmaniasis: re-emergence in patients with AIDS.

Leishmania infection may be associated with immunecomplex-mediated glomerular injury. Contrary to immune-competent individuals, leishmaniasis in HIV patients is a chronic, relapsing disease. Despite the increasing frequency of the Leishmania/ HIV co-infection, there is a paucity of information on the effects of such co-infection in the kidney. We present a patient with AIDS and refractory, relapsing visceral leishmaniasis who developed nephrotic syndrome associated with renal involvement by Leishmania in the absence of immunecomplex glomerular deposition. For the first time, the relapsing nature of renal injury in this context is documented.

[Fluid therapy in surgical patients: composition and influences on the internal milieu]. / Sueros empleados en enfermos quirúrgicos: composición y efectos sobre el medio interno.

UNLABELLED: Intravenous fluids administration is the usual practice in the postoperative period. Nonetheless, consensus about the more appropriate fluid reposition recipe is still insufficient. OBJECTIVE: To study the type of intravenous reposition used in Surgical Units and its impact on the internal milieu. DESIGN: prospective study of 112 patients with scheduled surgery, receiving only intravenous fluids. METHODS: biochemical study on postoperative fluids management in uncomplicated surgery. Principal variables: 1. Water and electrolytes administrated. 2. Differences in sodium/water balances before surgery vs first day after surgery. 3. Symptoms related to hyponatremia. RESULTS: Median P[Na] before and after surgery was 139.9+/-2.9 and 137.7+/-3.7, respectively (p<0.01). Fourteen patients (12.5%) had P[Na]<135, and 12 of them had a reduction of more than 6 mmol/L; accordingly, twenty-six patients (23.2%) had an increased free-water retention (p<0.05). Relevantly, they did not receive a higher amount of free-water and the proportion of isotonic saline/free water varied from <1 to >3. As possible mechanism of free-water accumulation: the postoperative P[Na] was lower in the patients who had a negative free-water clearance >or= -1 L (136.7+/-4.1 vs 138.5+/-3.2 mmol/L, p 0.015). CONCLUSION: The present study provides new information about the intravenous fluids prescribed in postoperative patients, ie, different proportions saline/water are basically equivalent with respect to inducing symptomatic hyponatremia. The mean value of the relation saline/water is 2:1. Hypotonic fluids input is not clearly related to more intense hyponatremia; the latter appears to depend more on a reduced capacity of the kidney to generate sufficient free water output.

[Renal infarction and kidney rupture: complication of a massive cocaine intoxication in an intestinal carrier]. / Infarto y rotura renales: complicación de intoxicación masiva por cocaína en un portador intestinal.

Major complications derived from the use of cocaine have been described, alter nasal or intravenous administration of the drug. These complications are related to vascular spasm and secondary organ damage. We present the case of an intestinal cocaine packer--in slang, "mule"--, who suffered massive absorption of the drug, resulting n bowel, liver and renal ischemia. This situation, previously undescribe in the literature, ended in kidney rupture. An attempt of embolization, was unsatisfactory, and nephrectomy was finally required. The patient recovered uneventfully, with progressive renal functional improvement. This case, albeit quite exceptional, is illustrative of several of the renal actions of cocaine, and reveals the effects of absorption of cocaine at the intestinal level.

Cilastatin protection against cyclosporin A-induced nephrotoxicity: clinical evidence.

BACKGROUND: Several studies have documented the nephroprotective effect of cilastatin co-administered with imipenem in subjects treated with cyclosporin A. However, no large clinical studies are available to confirm this observation. Here the quality of the evidence on cilastatin nephroprotection against cyclosporin-induced nephrotoxicity is evaluated. METHODS: The results of all studies where cyclosporin was used alone or combined with imipenem/cilastatin (Tienam) on the same clinical setting were systematically reviewed. Primary outcome was the reduction in serum creatinine concentration. Secondary outcome included development of acute renal failure. Medline was searched using three different retrieval systems (Pubmed, Silver Platter, Knowledge Finder) from January 1966 to February 2006. Attempts were made to contact authors of relevant studies to obtain additional data. Five clinical studies were found, including 125 patients under cyclosporin plus imipenem/cilastatin and 104 under cyclosporin alone. RESULTS: Cyclosporin increased serum creatinine in all the studies. Average reduction of serum creatinine in cilastatin-treated versus untreated patients was Delta = -0.53 mg/dL (95%CI: -0.90 to -0.17) (Z = 2.84, p = 0.004). Variability between studies was large (from Delta = -0.21 to Delta= -1.59 mg/dL) and heterogeneity pronounced (chi(2) = 8.760, df = 4; p = 0.067). Meta-regression of serum creatinine reduction versus baseline serum creatinine explained 84% of this variability, by the variation in basal serum creatinine. When randomized and observational clinical studies were analyzed separately, conclusions were the same: serum creatinine in cilastatin treated patients was reduced by Delta = -0.98 mg/dL (95%CI: -1.57 to -0.38) in randomized studies (Z = 3.213, p = 0.001) and Delta= -0.32 mg/dL (95%CI: -0.63 to -0.01) in observational studies (Z = 2.013, p = 0.044). Odds Ratio for developing acute renal failure was 0.24 (95% CI: 0.11-0.53, p < 0.0001) on patients simultaneously treated with cyclosporin plus imipenem/cilastatin compared to patients treated with cyclosporin alone. CONCLUSIONS: Administration of cilastatin may reduce acute cyclosporin nephrotoxicity.

Recurrent acute postinfectious glomerulonephritis.

Recurrent acute postinfectious glomerulonephritis is infrequent in childhood and exceptional in adults. The factors that determine recurrence are poorly understood. Selective IgA deficiency is characterized by an increased incidence of gastrointestinal and respiratory infections. The case of a 33-year-old man with a history of repetitive sinopulmonary infections and diagnosed with selective IgA deficiency is described. He suffered 2 episodes of postinfectious glomerulonephritis within a 15-year period. Selective IgA deficiency may have predisposed to the development of recurrent postinfectious glomerulonephritis

[Reticulocyte response after immediate withdrawal of recombinant human erythropoietin in chronic hemodialysis patients]. / Respuesta reticulocitaria tras cese inmediato de administración de eritropoyetina recombinante humana en enfermos en hemodiálisis crónica. Implicaciones en la terapia de la anemia.

UNLABELLED: The sudden interruption of recombinant human erythropoietin (rHuEPO) in end-stage renal disease (ESRD) patients leads to rapid anemization. The mechanisms of this phenomenon are, however, insufficiently understood. The present study examined the response to immediate rHuEPO withdrawal in dialysis patients. METHODS: 10 chronic hemodialysis (HD) patients regularly receiving rHuEPO were studied. rHuEPO was stopped and reinitiated after 7 days. Reticulocyte profile, haemoglobin and haematocrit were measured at 0, 7 and 15 days. As a complementary study, and with the purpose of analyzying whether uremia was a relevant factor, 10 non-uremic male Wistar rats were treated with rHuEPO. After two weeks, rHuEPO was withdrawn in 5 animals, and continued for 7 additional days in the remainder. The same variables than in the human study were determined. RESULTS: Changes in reticulocyte subtypes from baseline to day 7 were: total 18.2 +/- 0.9 vs 14.3 +/- 1.8% (p < 0.06); high-fluorescence (HFR): 2.6 +/- 0.4 vs 0.75 +/- 0.2 (p < 0.001); medium-fluorescence (MFR): 13.0 +/- 1.1 vs 6.6 +/- 0.9% (p < 0.02); and low-fluorescence (LFR): 84.2 +/- 1.4 vs 92.7 +/- 1% (p NS). The baseline pattern was recovered upon 7 days of rHuEPO reinitiation (p NS). Mean hemoglobin and hematocrit decreased by day 14 (p < 0.02) in spite of rHuEPO reinitiation at day 7. In non-uremic rats, changes were similar to that in the ESRD patients. CONCLUSION: rHuEPO induces changes in the reticulocyte pattern, consisting in a reduction of immature reticulocytes. These changes appear to be independent of the presence of uremia. Accordingly, complete rHuEPO withdrawal in HD patients will cause a rapidly-developing anaemia due to an alteration in the reticulocyte maturation series; therefore, sudden rHuEPO interruption should be avoided whenever is possible. As a collateral application, the specific changes described herein have potential use for detecting illegal administration of rHuEPO.

[Progressive deterioration in an elderly patient]. / Deterioro progresivo en paciente anciano.

Vasculitis is diagnosed with increasing frequency in the elderly. We hereby present the case of an 84-year-old male, who had weight loss, low-degree fever, anemia and epigastric pain. After 14 days of study with the tentative diagnosis of digestive neoplasia, a progressive renal insufficiency was detected. This clinical picture was secondary to ANCA-positive vasculitis. The case poses the differential diagnosis of non-oliguric acute renal failure (FRA) in elder people and the systematics of the study of renal insufficiency in individuals with previously unknown renal function. Also, this patient's history emphasizes the importance of acute deterioration of renal function as a guiding symptom for orienting the interpretation of clinical data. In the present case, a diagnostic hypothesis based only in the pursue of an occult digestive tumor misguided the attention from the main cause of the disease.

[Guidelines on hemodialysis-associated viral infections]. / Guías sobre enfermedades víricas en hemodiálisis (HD).

The viric infections influence morbi-mortality in Chronic kidney Disease patients in hemodialysis therapy and can affect to the Staff of the Units. The guides considered the most relevant virus at the present moment: C Virus, B Virus and HIV. To prevent horizontal nosocomial transmission is necessary the observance always the universal precautions in the HD units, although sometimes can appeared seroconversions and epidemic bud when exist a break of these. Is analyzed different situations with special focus in units for acute patients. The following steps under the suspicious of the epidemic bud appeared in one of the annexes together with legislation according to this case. Respect to the staff in every one of the virus is shown prevention patterns, serologic markers to perform when an accident with infected blood occur, also is considered when treatment is indicated. The guides considered too the conditions necessary for include these patients on waiting list for kidney transplantation.